Colorectal cancer (CRC) is a formidable disease due to the intricate mechanisms that drive its proliferation and metastasis. Despite significant progress in cancer research, the integration of these mechanisms that influence cancer cell behavior remains elusive. Therefore, it is imperative to comprehensively elucidate the underlying mechanisms driving CRC proliferation and metastasis. In this study, we reported a novel role of SLC26A3 in suppressing CRC progression. We found that SLC26A3 expression was downregulated in CRC, which was proportionally correlated with survival. Our in vivo and in vitro experiments demonstrated that up-regulation of SLC26A3 inhibited CRC proliferation and metastasis, while down-regulation of SLC26A3 promoted CRC progression by modulating the expression level of IκB. Furthermore, we identified NHERF2 as a novel interacting protein of SLC26A3 responsible for stabilizing the IκB protein and removing ubiquitination modification. Mechanistically, SLC26A3 augmented the interaction between NHERF2 and IκB, subsequently reducing its degradation. This process inhibited the dissociation of p65 from the IκB/p65/p50 complex and reduced the translocation of p65 from the cytoplasm to the nucleus. Moreover, our investigation revealed that NF-κB/p65 directly bound to the promoter of SLC26A3, leading to a decline in its mRNA expression. Thus, SLC26A3 impeded the nuclear translocation of NF-κB/p65, enhancing the transcription of SLC26A3 and establishing a positive regulatory feedback loop in CRC cells. Collectively, these results suggest that a SLC26A3/NHERF2-IκB/NF-κB/p65 signaling loop suppresses proliferation and metastasis in CRC cells. These findings propose a novel SLC26A3-driven signaling loop that regulates proliferation and metastasis in CRC, providing promising therapeutic interventions and prognostic targets for the management of CRC.

结直肠癌（CRC）是一种可怕的疾病，因为其增殖和转移的机制非常复杂。尽管癌症研究取得了重大进展，但影响癌细胞行为的这些机制的整合仍然难以捉摸。因此，全面阐明CRC增殖和转移的潜在机制势在必行。在这项研究中，我们报道了 SLC26A3 在抑制 CRC 进展中的新作用。我们发现 SLC26A3 表达在 CRC 中下调，这与生存率成比例相关。我们的体内和体外实验表明，SLC26A3的上调抑制CRC增殖和转移，而SLC26A3的下调通过调节IκB的表达水平促进CRC进展。此外，我们确定 NHERF2 是 SLC26A3 的一种新型相互作用蛋白，负责稳定 IκB 蛋白并消除泛素化修饰。从机制上讲，SLC26A3 增强了 NHERF2 和 IκB 之间的相互作用，随后减少了其降解。该过程抑制了 p65 从 IκB/p65/p50 复合物的解离，并减少了 p65 从细胞质到细胞核的易位。此外，我们的研究表明，NF-κB/p65 直接与 SLC26A3 的启动子结合，导致其 mRNA 表达下降。因此，SLC26A3阻碍了NF-κB/p65的核转位，增强了SLC26A3的转录并在CRC细胞中建立了正向调节反馈环。总的来说，这些结果表明 SLC26A3/NHERF2-IκB/NF-κB/p65 信号环路抑制 CRC 细胞的增殖和转移。这些发现提出了一种新的 SLC26A3 驱动的信号环路，可调节 CRC 的增殖和转移，为 CRC 的管理提供有前景的治疗干预措施和预后目标。